Development of Sustained-Release Anti-HIV Nucleoside Phosphonate Nanoparticles

项目摘要 尽管过去20年来药物开发取得了显著进展，但抗逆转录病毒治疗取得了成功 并不是通用的。治疗和预防环境中治疗失败的最常见原因 仍然是与药物依从性相关的挑战。尽管许多患者每天都可以 弱势群体长期坚持治疗疲劳以及特殊困难 患者群体，包括那些受到药物滥用、精神疾病、长期外出的挑战的人 来自家庭和社区内的耻辱。治疗失败的情况经常接踵而至。这导致了一种 对可长期给药的抗逆转录病毒化疗药物的开发越来越感兴趣 给药间隔时间。已经出现了几种新的化合物和合成方法，表明了这一点 目标是高度可实现的。在此应用程序中，我们希望开发一种有效的方法来交付全球 使用的核苷酸，替诺福韦，被列入可以每月间隔给药的药物名单。 我们已经证明，烷氧基烷基侧链与母体分子的酯键大大增强 细胞摄取，我们可以通过在细胞内添加第二个促进剂来改变细胞内的释放速率 剩下的磷酸盐氧。这些修饰的综合作用导致细胞快速摄取。 并将替诺福韦二磷酸持续“定时释放”释放到细胞内隔室。一次领先 替诺福韦十八烷氧基乙基苄基二酯(ODE-Bn-TFV)具有单一纳米分子抗HIV 活性和选择性指数为&gt；3000。替诺福韦二磷酸在细胞内缓慢释放 保持半衰期超过一周的隔间。我们建议利用这种方法来 开发更多效力更强、细胞内半衰期更长的化合物。我们将把我们的小说合成起来 纳米颗粒中的时间释放分子，将这些分子缓慢释放到体循环中 从肌肉注射的部位。我们认为，通过使用纳米技术首先调节释放 前体药物进入体循环，然后使用合成化学方法增强细胞摄取 为了减缓细胞内的腐烂，我们可以在一个月内向病毒复制部位传递强大的抗病毒活性 在肌肉注射之后。

Project Summary Despite the remarkable progress in drug development over the past 20 years, antiretroviral treatment success is not universal. The most frequent cause of treatment failure in both therapeutic and prophylactic settings continues to be challenges associated with drug adherence. Although many patients can manage daily adherence for substantial periods of time, treatment fatigue as well as special difficulties exist for vulnerable patient populations including those challenged by substance abuse, mental illness, prolonged periods away from home and stigma within their communities. All too often treatment failure ensues. This has led to an increasing interest in the development of antiretroviral chemotherapeutic agents that can be given at prolonged dosing intervals. Several novel compounds and compounding approaches have emerged that suggest this goal is highly attainable. In this application we wish to develop an effective approach to deliver the globally used nucleotide, tenofovir, to the list of agents that can be administered at monthly intervals. We have demonstrated that ester linkage of an alkoxyalkyl side chain to the parent molecule greatly enhances cellular uptake and that we can modify the rate of intracellular release by the addition of a second promoiety at the remaining phosphonate oxygen. The combined effect of these modifications results in rapid cellular uptake and sustained “timed-release” delivery of tenofovir diphosphate to the intracellular compartment. One lead compound, the octadecyloxyethyl benzyl diester of tenofovir (ODE-Bn-TFV), has single nanomolar anti-HIV activity and a selectivity index of >3000. Tenofovir diphosphate was slowly liberated in the intracellular compartment where it maintained a half-life of more than a week. We propose to utilize this approach to develop additional compounds of even greater potency and intracellular half-life. We will compound our novel time-release molecules in nanoparticles that will slowly release these molecules into the systemic circulation from the site of intramuscular injection. We believe that by using nanotechnology to first modulate release of prodrug into the systemic circulation and then using a synthetic chemical approach to enhance cellular uptake and to slow intracellular decay that we can deliver potent antiviral activity to sites of viral replication for a month following intramuscular injection.